Azapeptide inhibitor of HIV-1 protease.
Pharmacology: Resistance/Cross-Resistance: Resistance in Cell Culture: Atazanavir susceptibility was evaluated in clinical isolates from patients without prior atazanavir exposure and exhibiting a wide array of genotypic and phenotypic patterns. There was a clear trend toward decreased susceptibility to atazanavir as isolates exhibited high resistance levels to multiple protease inhibitors. In general, susceptibility to atazanavir was retained among isolates resistant to 1-2 protease inhibitors, despite the presence of primary substitutions associated with resistance to protease inhibitors.
Resistance In Vivo: Treatment-Naive Patients: Reyataz 400 mg without Ritonavir: The I50L substitution, sometimes in combination with an A71V change, is the signature resistance change for atazanavir. Of the 25 resistant isolates emerging in treatment-naive patient studies, 23 had an I50L susbstitution emerge on atazanavir therapy. There was no evidence of cross-resistance between atazanavir and amprenavir. Phenotypic analysis of the I50L-containing isolates showed atazanavir-specific resistance, which coincided with increased susceptibility to other protease inhibitors.
Reyataz 300 mg with Ritonavir 100 mg: In a study of treatment-naive patients comparing the efficacy of atazanavir plus ritonavir to lopinavir plus ritonavir, after 96 weeks of treatment, of the 30 isolates from patients with virologic failure without baseline substitutions, only 1/28 displayed phenotypic resistance to ATV (>5.2) with multipe PI substitutions (L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M) without emergence of I50L.
Treatment-Experienced Patients: Reyataz with or without Ritonavir: Approximately 80% and 100% of atazanavir-resistant isolates from experienced patients treated with atazanavir or the combination of atazanavir plus saquinavir, respectively, showed no evidence of the emergence of the I50L substitution, instead displaying decreased susceptibility to multiple protease inhibitors, which coincided with the accumulation of several additional amino acid substitutions, including I84V.
In studies of treatment-experienced patients treated with ATV/RTV, most ATV resistant isolates from patients who experienced virologic failure through 48 weeks developed substitutions that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease substitutions (>10% frequency) to develop in the viral isolates of patients who failed treatment with ATV 300 mg once daily and RTV 100 mg once daily [together with tenofovir and an nucleoside reverse transcriptase inhibitor (NRTI)] included L10F, K20I/M/V, V32I, M36I/L, M46I/L, I54V, A71V/T/I, G73S/T/C and V82A/T/L. Other substitutions that developed on ATV/RTV treatment including L24I, L33F/I/V, G48V, I50L/V, I84V and L90M occurred in <10% of patient isolates.
Pharmacokinetics: The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV-infected patients.
Absorption: Multiple dosing of Reyataz 400 mg once daily with a light meal produced peak steady-state atazanavir plasma concentrations approximately 2.7 hrs after administration. Steady state for atazanavir was achieved between day 4 and day 8.
Food Effect: Administration of Reyataz with food enhances bioavailability and reduces pharmacokinetic variability. Administration of Reyataz plus ritonavir with food optimizes the bioavailability of atazanavir.
Distribution: Atazanavir is 86% bound to human serum proteins.
Metabolism: Atazanavir is principally metabolized by the cytochrome P-450 3A4 (CYP3A4) isozyme to oxygenated metabolites. Metabolites are then excreted in the bile as either free or glucuronidated metabolites.
Elimination: Following a single 14C-atazanavir 400-mg dose, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy volunteers and HIV-infected adult patients was approximately 7 hrs.
Adolescents and Children: There are insufficient data at this time to recommend a dose (see Dosage & Administration: Adolescents and Children).
Toxicology: Nonclinical Safety: Carcinogenesis, Mutagenesis & Impairment of Fertility: Carcinogenicity studies with atazanavir were conducted in mice and rats. Mice were administered doses of 20, 40 and 80 mg/kg/day in males and 40, 120 and 360 mg/kg/day in females. In female mice, there was an increase in the incidence of benign hepatocellular adenomas at the highest dose. The exposure in female mice at the high dose is approximately 7 times exposure in humans given atazanavir 400 mg once daily.
No increase in the incidence of tumors was observed in female mice at lower doses or male mice at any dose. Exposures in male and female mice at nontumorigenic doses are approximately 4 times human exposure at 400 mg/day. In rats administered doses of 100, 350 and 1200 mg/kg/day, there was no increased incidence of any tumor type. Exposures in rats at the high dose are approximately 2 (males) and 6 (females) times exposure in humans given atazanavir 400 mg once daily. The increased incidence of benign hepatic adenomas in high-dose female mice was likely the result of increased hepatocellular proliferation secondary to cytotoxic liver changes (single-cell necrosis) and is considered to have no clinical relevance at human therapeutic exposures.
Atazanavir was negative in an Ames reverse-mutation assay but did induce chromosomal aberrations in vitro in both the absence and presence of metabolic activation. In in vivo studies in rats, atazanavir did not induce micronuclei in bone marrow, DNA damage in duodenum (comet assay) or unscheduled DNA repair in liver at plasma and tissue concentrations exceeding those that were clastogenic in vitro.
Atazanavir produced no effects on mating, fertility or early embryonic development in rats at doses that provided exposures equivalent to (males) and at least 2 times (females) exposure in humans given 400 mg once daily.